Treatment methods for solid tumors with mitogen-activated protein kinase (MAPK) pathway abnormalities

Abstract

The present disclosure provides a therapeutically effective amount of a mitogen-activated protein kinase (MAPK) inhibitor having the structure of the following compound: (I): [Formula 1] JPEG2026506133000036.jpg42165 or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 485,621, filed February 17, 2023, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Mutations leading to uncontrolled signaling through the RAS-RAF-MAPK pathway are found in more than one-third of all cancers. RAF kinases (A-RAF, B-RAF, and C-RAF) are essential parts of this pathway, and B-RAF mutations are common in clinical trials. Interestingly, certain types of B-RAF mutation-associated cancers are insensitive to FDA-approved B-RAF-selective drugs due to the function of other RAF family members. In particular, B-RAF-selective monotherapy fails to demonstrate clinical benefit against atypical B-RAF (non-V600E) and other RAF- and RAS-driven tumors.

[0003] There is a need in the art to provide alternative and improved methods for treating solid tumors that are insensitive to currently available B-RAF selective drugs.

[0004] The present application addresses these needs. Summary of the Invention

[0005] The present disclosure provides a method for treating cancer in a subject in need thereof. In particular, the present disclosure provides a method for treating a solid tumor by administering a pan-RAF inhibitor to a subject having a solid tumor that has one or more MAPK pathway abnormalities.

[0006] In one aspect, the disclosure provides a method of treating cancer, comprising administering to a patient from about 5 mg to about 1500 mg of Compound I: [ka] or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In embodiments, the subject is administered about 5 mg to about 500 mg of Compound I or a pharmaceutically acceptable salt thereof.

[0007] In an embodiment, compound I is [ka] is.

[0008] In embodiments, Compound I of the present disclosure has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0009] In embodiments, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, about 500 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered. In embodiments, about 20 mg to about 1000 mg or about 20 mg to about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In some embodiments, about 40 mg to about 1000 mg or about 40 mg to about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In some embodiments, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, or about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In some embodiments, about 1000 mg or about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day.

[0010] In embodiments, an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily. In embodiments, about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily. In embodiments, about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily. In embodiments, about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily. In embodiments, about 75 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily. In embodiments, about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0011] In embodiments, about 250 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily. In embodiments, about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily.

[0012] In embodiments, an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is orally administered in the form of a pharmaceutical formulation. In embodiments, the pharmaceutical formulation is a tablet or capsule. In embodiments, the pharmaceutical formulation is a capsule. In embodiments, the pharmaceutical formulation comprises about 5 mg to about 50 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical formulation comprises about 10 mg or about 25 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0013] In embodiments, the cancer is an advanced or metastatic cancer. In embodiments, the cancer is selected from the group consisting of Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, primary CNS tumors, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumors (metastasis to the central nervous system of tumors arising outside the central nervous system), brain tumors, brain metastases, colorectal cancer, colorectal cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AM). L); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; melanoma; neurofibromatosis type 1 (NF1); neurofibromatosis type 2 (NF2); esophageal cancer; bladder cancer; mesothelioma; or thyroid cancer. In embodiments, the cancer is non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, or pancreatic cancer. In some embodiments, the melanoma is metastatic melanoma.

[0014] In some embodiments, the cancer comprises a solid tumor that has one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway. In some embodiments, the one or more abnormalities are KRAS mutation, NRAS mutation, HRAS mutation, BRAF mutation, BRAF fusion, BRAF translocation, ARAF mutation, RAF mutation, increased receptor tyrosine kinase (RTK) signaling, RAS gene amplification, RAF gene amplification, or a combination thereof. In some embodiments, the KRAS mutation is G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof. In embodiments, NRAS mutations include Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof. In embodiments, HRAS mutations include Q61R, Q61K, Q61L, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof. In embodiments, the ARAF mutations include G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof. In embodiments, the BRAF mutations include class 1 BRAF mutations, class 2 BRAF mutations, class 3 BRAF mutations, or a combination thereof. In embodiments, the BRAF mutations include class 2 or 3 BRAF mutations.In embodiments, the BRAF mutations include V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof. In embodiments, the RAF mutations include S257L / W, S259F, R391S / W, or a combination thereof. In embodiments, the one or more abnormalities include NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

[0015] In another aspect, the disclosure provides a method of treating cancer harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway in a subject, comprising detecting one or more abnormalities in the MAPK pathway; and then administering about 5 mg to about 1500 mg of Compound I: [ka] or a pharmaceutically acceptable salt thereof, is administered to a subject. In embodiments, the subject is administered about 5 mg to about 500 mg of Compound I or a pharmaceutically acceptable salt thereof.

[0016] In an embodiment, compound I is [ka]

[0017] In embodiments, Compound I of the present disclosure has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0018] In embodiments, the disclosed methods provide a treatment that reduces tumor size compared to the tumor size before administration. In embodiments, the treatment increases the overall response rate (ORR) compared to the ORR of otherwise similar patients with cancer who have not been treated with Compound I. In embodiments, the treatment increases progression-free survival (PFS) compared to PFS of otherwise similar patients with cancer who have not been treated with Compound I. In embodiments, the treatment increases overall survival (OS) compared to OS of otherwise similar patients with cancer who have not been treated with Compound I.

[0019] In embodiments, the treatment reduces tumor size by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% compared to the tumor size before administration. In embodiments, the treatment increases ORR by at least about 5%. In embodiments, the treatment increases ORR by 10% to about 100%. In embodiments, the treatment extends PFS by at least about 3 months. In embodiments, the treatment extends PFS by at least about 6 months, 12 months, at least about 18 months, or at least about 24 months. In embodiments, the treatment increases OS by at least about 3 months.

[0020] In embodiments, the present disclosure provides a method of treating a cancer expressing one or more ARAF mutants in a subject in need thereof, comprising administering to the subject in need thereof an equivalent dose of about 5 mg to about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the equivalent dose of about 5 mg to about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered to the subject.

[0021] In embodiments, the present disclosure provides a method of treating berbalafenib-resistant cancer in a subject in need thereof, comprising administering to the subject in need thereof an equivalent dose of about 5 mg to about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the equivalent dose of about 5 mg to about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered to the subject. [Brief explanation of the drawings]

[0022] [Figure 1] Figures A-E show the change in tumor size (mm3) after administration of Compound I (Comp1) at 10 mg / kg (bid), 30 mg / kg (bid), 30 mg / kg (qd), or 100 mg / kg (qd) to xenografted mice bearing NRAS, KRAS, or BRAF class 2 / 3 mutation-driven colorectal cancer (CRC) (Figure 1A), non-small cell lung cancer (NSCLC) (Figure 1B), melanoma (Figure 1C), or ovarian cancer (Figure 1D), as described in Example 3. Vehicle was administered bid as a control. Figure 1E shows the change in tumor volume observed after administration of Compound I at 10 mg / kg (bid), 30 mg / kg (bid), or 100 mg / kg (qd) to the ovarian cancer xenografted mice shown in Figure 1D. Compared to the vehicle control, P<0.001 is indicated by "***" and P<0.0001 is indicated by "****." [Figure 2] 1 shows a schematic diagram of Parts A and B of the Phase 1 study described in Example 4. Abbreviations: MTD = maximum tolerated dose, NSCLC = non-small cell lung cancer, RP2D = recommended Phase 2 dose. [Figure 3] 1 shows positron emission tomography-computed tomography (PET / CT) images of a cancer patient before and after Compound I treatment, as described in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0023] All publications, patents, and patent applications in this specification, including any drawings and exhibits, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or exhibit was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0024] definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate the description of the subject matter disclosed herein.

[0025] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] The term "about" immediately preceding a numerical value denotes a range (e.g., ±10% of that value). For example, unless the context of the disclosure dictates otherwise or contradicts such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55, ...," "about 50" means a range spanning less than half the interval(s) of the preceding or following values, e.g., a range greater than 49.5 and less than 52.5. Furthermore, expressions such as "about," "less than," or "about," "greater than" a value should be understood in light of the definition of the term "about" provided herein. Similarly, the term "about" before a series of numerical values ​​or ranges of values ​​(e.g., "about 10, 20, 30," or "about 10 to 30") refer to the endpoints of all values ​​in the series or ranges, respectively. As used herein, the term "substantially" means greater than 85% (i.e., greater than 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%).

[0027] As used herein, Compound I is 5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one, having the structure shown below. [ka]

[0028] All references herein to Compound I include all of its stereoisomers and tautomers. In embodiments, Compound I includes its stereoisomers. In embodiments, Compound I is (S)-5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one, having the structure shown below. [ka]

[0029] In embodiments, Compound I of the present disclosure has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0030] Compound I can be prepared according to the method disclosed in WIPO Patent Application Publication No. 2022 / 023450, the entirety of which is incorporated herein.All references to Compound I herein also include its pharmaceutically acceptable salts.In an embodiment, Compound I is a pan-RAF inhibitor.

[0031] The term "treating" refers to one or more of alleviating, mitigating, delaying, reducing, ameliorating, improving, or managing at least one symptom of a condition in a subject. The term "treating" can also refer to one or more of preventing, delaying the onset (i.e., the period before clinical signs of a pathology), or reducing the risk of development or worsening of a condition.

[0032] As used herein, a daily dosage can be achieved by administering a single target dose or by administering multiple smaller doses over a 24-hour period. For example, a daily dosage of 150 mg can be achieved by administering a single dose of 150 mg of a therapeutic agent per day, two doses of 75 mg of a therapeutic agent per day, or three doses of 50 mg of a therapeutic agent per day, etc.

[0033] As used herein, the term "therapeutically effective amount" or the like refers to the amount required to be administered to a patient, or to a patient's cells, tissues, or organs, to produce a therapeutic effect, such as an ameliorative or curative effect in the treatment of cancer. A therapeutically effective amount is an amount sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0034] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt or stereoisomer. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge, et al., provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977), 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0035] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N(C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0036] The term "equivalent dose" refers to a dose containing the same amount of Compound I within about 5% (wt %) when comparing Compound I to a salt form.

[0037] As used herein, the terms "diagnose," "diagnosis," and "diagnosing" refer to identifying, assessing, evaluating, or classifying the presence or characteristics of a pathological condition, e.g., diagnosing whether a subject referred to in accordance with the methods of the present disclosure has one or more abnormalities in the MAPK signaling pathway.

[0038] The term "subject" or "patient" refers to a mammal. In embodiments, the subject is a human.

[0039] The following description contains information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0040] Methods of the present disclosure Abnormal activation of the MAPK pathway can drive human cancer through promoting cell proliferation and growth. Mutations in genes involved in this pathway, including RAS and RAF, are common in human cancers, such as melanoma, NSCLC, colorectal cancer, and pancreatic cancer, particularly solid tumors. The most common mutations in the MAPK pathway occur in RAS protein kinases (KRAS, NRAS, and HRAS), leading to the constitutive activation of downstream effector RAF proteins (ARAF, BRAF, and CRAF). Although RAF-selective inhibitors (e.g., vemurafenib, dabrafenib, and encorafenib) have been developed for cancer treatment, the clinical efficacy of these inhibitors is limited by the development of drug resistance at various steps in the MAPK signaling pathway and limited or no activity against ARAF and ARAF mutants. These limitations of BRAF-selective inhibitors highlight the need for agents that can inhibit the aberrant activation of all RAF proteins, including the three classes of RAF mutants: BRAF V600E (class I), BRAF-CRAF dimer (class II), and RAF dimer-dependent mutants.

[0041] The present applicant surprisingly discovered that Compound I is a pan-RAF inhibitor. The applicant's experimental results showed that Compound I is significantly more potent than known pan-RAF inhibitors in inhibiting the kinase activity of all three RAF isoforms. One of the most studied pan-RAF inhibitors is belvarafenib, a type II pan-RAF inhibitor currently undergoing clinical trials for the treatment of BRAF V600E and NRAS-mutated melanoma. Belvarafenib has demonstrated preclinical efficacy in reducing tumor growth, but acquired resistance has also been demonstrated in certain cancers. Combining biochemical and genomic studies has revealed that recurrent mutations in ARAF (e.g., Gly377 or Gly387 mutations) are one of the most important factors conferring resistance to belvarafenib. (Yen, I., et al., ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma, Nature, 2021 Vol. 594 418-423).

[0042] The present applicant surprisingly discovered that Compound I exhibits 2-10 times greater potency than other pan-RAF inhibitors (e.g., berbalafenib and naporafenib) in inhibiting the kinase activity of ARAF, including ARAF mutants, and that the development of resistance to berbalafenib is associated with the development of resistance. Without being bound by theory, these above-described findings provide an effective dosing regimen for Compound I for various forms of cancer harboring mutations in the MAPK pathway. In embodiments, the disclosed dosing regimen effectively treats various forms of cancer harboring mutations in the MAPK pathway while minimizing side effects. In other words, the disclosed dosing regimen achieves an acceptable benefit-risk ratio.

[0043] In embodiments, the present application describes a safe and effective dosing regimen of Compound I, or a pharmaceutically acceptable salt thereof, to provide anti-tumor activity in subjects with solid tumors harboring abnormalities in the MAPK pathway.

[0044] In one aspect, the disclosure provides a method of treating cancer, comprising administering to a patient a compound I having the following chemical structure: [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof. In embodiments, Compound I is [ka] In embodiments, Compound I of the present disclosure has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0045] In embodiments, the present disclosure provides a method of treating a cancer harboring one or more ARAF mutations in a subject in need thereof, comprising administering to a subject in need thereof an equivalent dose of about 5 mg to about 1500 mg (e.g., 5-500 mg or 30-500 mg) of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating a cancer harboring one or more ARAF mutations in a subject in need thereof, comprising administering to a subject in need thereof an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the ARAF mutation comprises G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof. In embodiments, the ARAF mutation comprises P462L, G377R, G387D, or a combination thereof. In embodiments, compound I or a pharmaceutically acceptable salt thereof is administered at a dose that provides a steady-state plasma concentration sufficient to inhibit the activity of the ARAF mutant.

[0046] In embodiments, the present disclosure provides a method of treating berbalafenib-resistant cancer in a subject in need thereof, comprising administering to the subject in need thereof an equivalent dose of about 5 mg to about 1500 mg of Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating berbalafenib-resistant cancer in a subject in need thereof, comprising administering to the subject in need thereof an equivalent dose of about 5 mg to about 500 mg of Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the berbalafenib-resistant cancer expresses an ARAF mutant. In embodiments, the ARAF mutant comprises a P462L, G377R, G387D mutation, or a combination thereof.

[0047] In embodiments, the present disclosure provides a method of treating naporafenib-resistant cancer in a subject in need thereof, comprising administering to a subject in need thereof an equivalent dose of about 5 mg to about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method of treating naporafenib-resistant cancer in a subject in need thereof, comprising administering to a subject in need thereof an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the naporafenib-resistant cancer expresses an ARAF mutant.

[0048] In an embodiment, compound I is [ka]

[0049] In embodiments, the cancer is an advanced or metastatic cancer. In embodiments, the cancer comprises a solid tumor. In embodiments, the cancer harbors an abnormality in the MAPK pathway. In embodiments, the cancer harbors an abnormality in the MAPK pathway.

[0050] In embodiments, the therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, administered to a subject is an equivalent dose of 1 mg to about 2000 mg (e.g., about 1 mg to about 1900 mg, about 1 mg to about 1800 mg, about 1 mg to about 1700 mg, about 1 mg to about 1600 mg, about 1 mg to about 1500 mg, about 1 mg to about 1400 mg, about 1 mg to about 1300 mg, about 1 mg to about 1200 mg, about 1 mg to about 1100 mg, about 1 mg to about 1000 mg, about 1 mg to about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg ~500mg, 1mg~400mg, 1mg~300mg, 1mg~200mg, 1mg~100mg, 1mg~90mg, 1mg~80mg, 1mg~70mg, 1mg~60mg, 1mg~50mg, 1mg~40mg, 1 mg~30mg, 1mg~20mg, 1mg~10mg, 5mg~2000mg, 5mg~1900mg, 5mg~1800mg, 5mg~1700mg, 5mg~1600mg, 5mg~1500mg, 5mg~1400mg, 5m g ~ about 1300mg, about 5mg - about 1200mg, about 5mg - about 1100mg, about 5mg - about 1000mg, about 5mg - about 900mg, about 5mg - about 800mg, about 5mg - about 700mg, about 5mg - about 600mg, about 5mg - about 500mg, about 5mg - about 400 300mg, about 5mg to about 200mg, about 5mg to about 100mg, about 5mg to about 90mg, about 5mg to about 80mg, about 5mg to about 70mg, about 5mg to about 60mg, about 5mg to about 50mg, about 5mg to about 40mg, about 5mg to about 30mg, about 5mg to about 20mg, about 5mg to about 1 0mg, about 10mg to about 2000mg, about 10mg to about 1900mg, about 10mg to about 1800mg, about 10mg to about 1700mg, about 10mg to about 1600mg, about 10mg to about 1500mg, about 10mg to about 1400mg, about 10mg to about 1300mg, about 10mg to about 1 200mg, about 10mg to about 1100mg, about 10mg to about 1000mg, about 10mg to about 900mg, about 10mg to about 800mg, about 10mg to about 700mg, about 10mg to about 600mg, about 10mg to about 500mg, about 10mg to about 400mg, about 10mg to about 300mg,Approximately 10mg to approximately 200mg, approximately 10mg to approximately 100mg, approximately 10mg to approximately 90mg, approximately 10mg to approximately 80mg, approximately 10mg to approximately 70mg, approximately 10mg to approximately 60mg, approximately 10mg to approximately 50mg, approximately 10mg to approximately 40mg, approximately 10mg to About 30mg, about 10mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 1900mg, about 20mg to about 1800mg, about 20mg to about 1700mg, about 20mg to about 1600mg, about 20mg to about 1500mg, about 2 0mg to about 1400mg, about 20mg to about 1300mg, about 20mg to about 1200mg, about 20mg to about 1100mg, about 20mg to about mg, about 20mg to about 900mg, about 20mg to about 800mg, about 20mg to about 700mg, about 20mg to about 600mg, about 20mg to about 500mg, about 20mg to about 400mg, about 20mg to about 300mg, about 20mg to about 200mg, about 20mg to about 100mg, about 20mg to about 90mg, about 20mg to about 80mg, about 20 mg ~ about 70mg, about 20mg - about 60mg, about 20mg - about 50mg, about 20mg - about 40mg, about 20mg - about 30mg, about 40mg - about 2000mg, about 40mg - about 1900mg, about 40mg - about 1800mg, about 40mg ~1700mg, 40mg~1600mg, 40mg~1500mg, 40mg~1400mg, 40mg~1300mg, 40mg~1200mg, 40mg~1100mg, 40mg~1000 mg, about 40 mg to about 900 mg, about 40 mg to about 800 mg, about 40 mg to about 700 mg, about 40 mg to about 600 mg, about 40 mg to about 500 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 40 mg to about 100 mg, about 40 mg to about 90 mg, about 40 mg to about 80 mg, about 40 mg to about 70 mg, about 40 mg to about 60 mg, or about 40 mg to about 50 mg (including any value or range therebetween). In an embodiment, a dose equivalent to about 5 mg to about 1500 mg of Compound I or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a dose equivalent to about 5 mg to about 500 mg of Compound I or a pharmaceutically acceptable salt thereof is administered to a subject. In an embodiment, a dose equivalent to about 20 mg to about 1000 mg of Compound I,In an embodiment, about 40 mg to about 1000 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In an embodiment, about 20 mg to about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In an embodiment, about 20 mg to about 300 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day. In an embodiment, about 20 mg to about 200 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered per day.

[0051] In embodiments, the therapeutically effective amount of Compound I, or an equivalent dose of a pharmaceutically acceptable salt or stereoisomer, administered to a subject is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900, or about 2000 mg (including any value or range therebetween). In embodiments, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, about 500 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 5 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once a day. In some embodiments, about 20 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once a day. In one embodiment, about 25 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, about 30 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily.In embodiments, about 40 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 50 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 60 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 75 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 100 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 150 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 175 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 200 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 225 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 275 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 325 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 375 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 425 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 475 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. In embodiments, about 1000 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily.

[0052] In an embodiment, an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily. In an embodiment, about 5 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 5 mg). In an embodiment, about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 20 mg). In an embodiment, about 25 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 25 mg). In an embodiment, about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 30 mg). In an embodiment, about 40 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 40 mg). In an embodiment, about 50 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 50 mg). In an embodiment, about 75 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 75 mg). In an embodiment, about 100 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 100 mg). In an embodiment, about 150 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 150 mg). In an embodiment, about 175 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 175 mg). In an embodiment, about 200 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. (i.e., a total daily dose of 200 mg). In an embodiment, about 225 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. (i.e., a total daily dose of 225 mg). In an embodiment, about 275 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. (i.e., a total daily dose of 275 mg). In an embodiment, about 325 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily. (i.e., a total daily dose of 325 mg).In an embodiment, about 375 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 375 mg). In an embodiment, about 425 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 425 mg). In an embodiment, about 475 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 475 mg). In an embodiment, about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 500 mg).

[0053] In an embodiment, about 5 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 10 mg). In an embodiment, about 20 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 40 mg). In an embodiment, about 25 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 50 mg). In an embodiment, about 30 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 60 mg). In an embodiment, about 40 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 80 mg). In an embodiment, about 50 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 100 mg). In an embodiment, about 75 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 150 mg). In an embodiment, about 100 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 200 mg). In an embodiment, about 150 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered once daily (i.e., a total daily dose of 300 mg). In an embodiment, about 175 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 350 mg). In an embodiment, about 200 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 400 mg). In an embodiment, about 225 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily. (i.e., a total daily dose of 450 mg). In an embodiment, about 250 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily. (i.e., a total daily dose of 500 mg). In an embodiment, about 275 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily. (i.e., a total daily dose of 550 mg). In an embodiment, about 325 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily.(i.e., a total daily dose of 650 mg). In an embodiment, about 350 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 700 mg). In an embodiment, about 375 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 750 mg). In an embodiment, about 425 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 850 mg). In an embodiment, about 475 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 950 mg). In an embodiment, about 500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, is administered twice daily (i.e., a total daily dose of 100 mg). In embodiments, an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered in any one of the following dosing regimens: [Table 1]

[0054] In embodiments, the cancer is Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma; astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastasis to the central nervous system of tumors arising outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colorectal cancer; gastric cancer; head and neck cancer; head and neck squamous cell carcinoma; acute lymphoblastic leukemia; acute myeloid leukemia (AM). L); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; melanoma; neurofibromatosis type 1 (NF1); neurofibromatosis type 2 (NF2); esophageal cancer; bladder cancer; mesothelioma; or thyroid cancer.

[0055] In embodiments, the cancer is non-small cell lung cancer (NSCLC). In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is melanoma. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is advanced or metastatic cancer. In some embodiments, the melanoma is metastatic melanoma. In embodiments, the cancer is thyroid cancer. In embodiments, the thyroid cancer is papillary, follicular, Hürthl cell, medullary, or anaplastic thyroid cancer.

[0056] In embodiments, the cancer comprises a solid tumor harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway, in which the one or more abnormalities comprise a KRAS mutation, an NRAS mutation, an HRAS mutation, a BRAF mutation, a BRAF fusion, a BRAF rearrangement, an ARAF mutation, a RAF mutation, increased receptor tyrosine kinase (RTK) signaling, a RAS gene amplification, a RAF gene amplification, or a combination thereof.

[0057] In embodiments, KRAS mutations include G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof. In embodiments, NRAS mutations include Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof. In embodiments, the HRAS mutation comprises Q61R, Q61K, Q61L, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0058] In embodiments, the ARAF mutations include G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

[0059] In embodiments, the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof. In embodiments, the BRAF mutation comprises a class 2 or 3 BRAF mutation. In embodiments, the BRAF mutations include V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

[0060] In embodiments, the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof. In embodiments, the one or more abnormalities comprise NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

[0061] In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered for at least about 14 days, e.g., 2 weeks, or 3 weeks, or 4 weeks, or 5 weeks, or 6 weeks, or 7 weeks, or 8 weeks, or 9 weeks, or 10 weeks, or 11 weeks, or 12 weeks, or 13 weeks, or 14 weeks, or 15 weeks, or 16 weeks, or 17 weeks, or 18 weeks, or 19 weeks, or 20 weeks, or 21 weeks, or 22 weeks, or 23 weeks, or 24 weeks, or 25 weeks, or 26 weeks, or 7 weeks, or 28 weeks, or 29 weeks, or 30 weeks, or 31 weeks, or 32 weeks, or 33 weeks, or 34 weeks, or 35 weeks, or 36 weeks, or 37 weeks, or 38 weeks, or 39 weeks, or 40 weeks, or 41 weeks, or 42 weeks, or 43 weeks, or 44 weeks, or 45 weeks, or 46 weeks, or 47 weeks, or 48 weeks, or 49 weeks, or 50 weeks, or 51 weeks, or 52 weeks, or 53 weeks, or 54 weeks, or 55 weeks, or 56 weeks , or 57 weeks, or 58 weeks, or 59 weeks, or 60 weeks, or 61 weeks, or 62 weeks, or 63 weeks, or 64 weeks, or 65 weeks, or 66 weeks, or 67 weeks, or 68 weeks, or 69 weeks, or 70 weeks, or 71 weeks, or 72 weeks, or 73 weeks, or 74 weeks, or 75 weeks, or 76 weeks, or 77 weeks, or 78 weeks, or 79 weeks, or 80 weeks, or 81 weeks, or 82 weeks, or 83 weeks, or 84 weeks, or 85 weeks, or is administered for 86 weeks, or 87 weeks, or 88 weeks, or 89 weeks, or 90 weeks, or 91 weeks, or 92 weeks, or 93 weeks, or 94 weeks, or 95 weeks, or 96 weeks, or 97 weeks, or 98 weeks, or 99 weeks, or 100 weeks, or 101 weeks, or 102 weeks, or 103 weeks, or 104 weeks, or 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, or more.

[0062] In embodiments, the disclosure provides a method of treating cancer in a subject harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway, comprising detecting one or more abnormalities in the MAPK pathway; and then administering about 5 mg to about 1500 mg of Compound I, having the following chemical structure: [ka] or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a method for treating a cancer harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway in a subject, the method comprising detecting one or more abnormalities in the MAPK pathway; and then administering to the subject about 5 mg to about 1500 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof.

[0063] In an embodiment, compound I is [ka] is.

[0064] In embodiments, Compound I of the present disclosure has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0065] In embodiments, the one or more abnormalities comprise a KRAS mutation, an NRAS mutation, an HRAS mutation, a BRAF mutation, a BRAF fusion, a BRAF rearrangement, an ARAF mutation, a RAF mutation, increased receptor tyrosine kinase (RTK) signaling, a RAS gene amplification, a RAF gene amplification, or a combination thereof.

[0066] In embodiments, KRAS mutations include G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof. In embodiments, NRAS mutations include Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof. In embodiments, the HRAS mutation comprises Q61R, Q61K, Q61L, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0067] In embodiments, the ARAF mutations include G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

[0068] In embodiments, the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof. In embodiments, the BRAF mutation comprises a class 2 or 3 BRAF mutation. In embodiments, the BRAF mutations include V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

[0069] In embodiments, the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof. In embodiments, the one or more abnormalities comprise NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

[0070] In embodiments, the one or more abnormalities are detected and quantified using a suitable method, such as real-time quantitative polymerase chain reaction (RT-PCR), immunohistochemistry, and / or Western blot, as described in U.S. Pat. No. 9,567,640 and U.S. Pat. No. 8,232,062, the entireties of which are incorporated herein by reference.

[0071] Pharmaceutical Compositions and Formulations In embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In embodiments, the pharmaceutical composition of the present disclosure is formulated for oral, intravenous, intramuscular, subcutaneous, or parenteral administration.

[0072] In embodiments, Compound I or a pharmaceutical composition of the present disclosure is administered orally in the form of a tablet, capsule, syrup, powder, or granules. In embodiments, an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is orally administered in the form of a pharmaceutical formulation. In embodiments, the pharmaceutical composition may be a solid, powder, liquid, or gel. In embodiments, the pharmaceutical composition is a solid (e.g., a powder, tablet, capsule, granule, and / or aggregate). In certain such embodiments, the solid pharmaceutical composition comprises one or more excipients known in the art, including, but not limited to, starch, sugar, diluent, granulating agent, lubricant, binder, and disintegrant. In embodiments, the pharmaceutical formulation is a tablet or capsule. In embodiments, the pharmaceutical formulation is a capsule.

[0073] For oral administration, Compound I or its pharmaceutically acceptable salt or stereoisomer may be mixed with, for example, lactose, saccharose, sorbitol, mannitol; starch, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide. Alternatively, tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0074] For the preparation of soft gelatin capsules, Compound I or a salt thereof can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using any of the tablet excipients described above. Alternatively, liquid or semisolid formulations of Compound I or a salt thereof can be filled into hard gelatin capsules. Liquid preparations for oral administration may be in the form of a syrup or suspension, for example, a solution containing Compound I or a salt thereof with the remainder being a mixture of sugar, ethanol, water, glycerol, and propylene glycol. Such liquid preparations may optionally contain colorants, flavors, sweeteners (e.g., saccharin), preservatives, and / or carboxymethylcellulose as a thickener, or other excipients known to those skilled in the art.

[0075] In embodiments, the pharmaceutical formulation contains Compound I in an amount of about 1 mg to about 500 mg, or an equivalent dose of a pharmaceutically acceptable salt thereof, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about In an embodiment, the pharmaceutical formulation comprises an equivalent dose of about 5 mg to about 200 mg of Compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical formulation comprises about 5 mg to about 100 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical formulation comprises about 5 mg to about 50 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical formulation comprises about 10 mg to about 25 mg of Compound I, or an equivalent dose of a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical composition comprises about 25 mg of Compound I, or a pharmaceutically acceptable salt and / or solvate thereof.

[0076] In embodiments, the pharmaceutical compositions may contain additional materials useful in physically formulating various dosage forms of the compositions of the present disclosure, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickeners, stabilizers, lubricants, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, flavoring and / or aromatic substances, but do not include additional anti-tumor agents.

[0077] Combination therapy In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in combination with one or more therapeutic agents.

[0078] In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in combination with one or more targeted therapeutic agents. In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in combination with immune effector cells (e.g., T cells, NK cells) engineered to contain one or more chimeric antigen receptors (CARs) and one or more targeted therapeutic agents. Multiple types of cells may be contemplated as targeted therapeutic agents, for example, CAR T cells, genetically modified T cells, tumor-infiltrating lymphocytes (TILs), vaccines, and / or natural killer (NK) cells. In embodiments, the one or more targeted therapeutic agents include gene therapy agents, including agents used in methods to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2.

[0079] In embodiments, the one or more targeted therapeutic agents are selected from the group consisting of ALK inhibitors (e.g., alectinib, brigatinib, ceritinib, and crizotinib); angiogenesis inhibitors (e.g., aquitinib, cabozantinib, cabozantinib, levatinib, pazopanib, regorafenib, sorafenib, sunitinib, vandetanib, and ziflibercept); BCR-ABL kinase inhibitors (e.g., bosutinib, dasatinib, imatinib mesylate, nilotinib, and ponatinib); BRAF and MEK inhibitors (e.g., binimetinib, cobimetinib, dabrafenib, and dabrafenib); BTK inhibitors (e.g., acalabrutinib and ibrutinib); cyclin-dependent kinase inhibitors (e.g., abemaciclib, palbociclib, and ribociclib); EGFR inhibitors (e.g., afatinib, erlotinib, gefitinib, lapatinib, neratinib, and osimertinib); PARP inhibitors (e.g., olaparib, niraparib, and rucaparib); PI3K inhibitors (e.g., duvelisib, copanlisib, perifosine, and idelalisib), or combinations thereof.

[0080] In embodiments, the one or more therapeutic agents include an anti-tumor agent. In embodiments, the additional therapeutic agent is an anti-proliferative / anti-tumor agent. In embodiments, the anti-proliferative / anti-tumor agent is selected from the group consisting of alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine, fluoropyrimidines such as 5-fluorouracil and tegafur, folate antagonists such as raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, fluticasone, fluoxetine ... anthracyclines such as bicine, idarubicin, mitomycin-C, dactinomycin, and mithramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polo kinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; or topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin).

[0081] In embodiments, the one or more therapeutic agents include a cytostatic agent, which is an anti-estrogen (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), an anti-androgen (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), an LHRH antagonist or agonist (e.g., goserelin, leuprorelin, and buserelin), a progestogen (e.g., megestrol acetate), an aromatase inhibitor (e.g., anastrozole, letrozole, vorazole, and exemestane), or an inhibitor of 5α-reductase, such as finasteride.

[0082] In embodiments, the one or more therapeutic agents include an anti-invasive agent, hi embodiments, the anti-invasive agent is dasatinib and bosutinib (SKI-606), a metalloproteinase inhibitor, or an inhibitor of urokinase plasminogen activator receptor function, or an antibody against heparanase.

[0083] In embodiments, the one or more therapeutic agents include inhibitors of growth factor function. In embodiments, inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, e.g., the anti-erbB2 antibody trastuzumab (Herceptin™), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of cellular apoptosis. inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., farnesyltransferase inhibitors, RAS / RAF signaling inhibitors such as sorafenib, tipifarnib, and lonafarnib); inhibitors of cell signaling via MEK and / or AKT kinases, C-kit inhibitors, abl kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; and cyclin-dependent kinase inhibitors such as Aurora kinase inhibitors or CDK2 and / or CDK4 inhibitors.

[0084] In embodiments, the one or more therapeutic agents include an anti-angiogenic agent that inhibits the effects of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib.

[0085] In embodiments, the one or more therapeutic agents comprises a cytotoxic agent, hi embodiments, the cytotoxic agent is fludarivine (Fludara), cladribine, or pentostatin (Nipent™).

[0086] In embodiments, the one or more therapeutic agents comprise a steroid. In embodiments, the steroid is a corticosteroid, including glucocorticoids and mineralocorticoids, such as aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, deoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide ... Examples of suitable steroids include fluocortin butyl, fluorocortisone, fluorocortolone, flucortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, icometasone embutate, meprednisone, methylprednisolone, paramethasone mometasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids, such as combinations of two or more of the steroids described herein, may also be used.

[0087] In embodiments, the one or more therapeutically active agents are immunotherapeutic agents. In embodiments, the immunotherapeutic agent is an interferon or a colony-stimulating factor. In embodiments, the immunotherapeutic agent is a PD-1 or PDL-1 inhibitor (e.g., nivolumab, cemilimab, dostarimab, sintilimab, atezolizumab, avelumab, and durvalumab); a CTLA-4 inhibitor (e.g., ipilimumab and tremelimumab); or a LAG-3 inhibitor such as leratilimab.

[0088] In embodiments, the one or more therapeutic agents comprise an antibody-drug conjugate (e.g., trastuzumab emtansine, trastuzumab derxistecan, enfortuzumab vedotin, and sacituzumab govitecan).

[0089] In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered simultaneously with one or more therapeutic agents. In embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered sequentially with one or more therapeutic agents.

[0090] Clinical outcomes In embodiments, the disclosed methods reduce the size of one or more tumors (referred to as "tumor size" or "tumor volume") compared to the tumor size before administration. In embodiments, the treatment reduces tumor size by about 10% to about 95%, about 15% to about 95%, about 20% to about 95%, about 30% to about 95%, about 40% to about 95%, about 50% to about 95%, or by at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100% (including any value or range therebetween) compared to the tumor size before administration. In embodiments, changes in tumor size are detected and quantified using computed tomography (CT) scans, positron emission tomography-computed tomography (PET / CT) scans, MRI scans, or X-ray scans, as determined by Response Evaluation Criteria in Solid Tumors (RECIST).

[0091] In embodiments, the disclosed methods provide a treatment that stabilizes tumor size. In embodiments, the treatment maintains the size of the tumor, such that the size of the tumor after administration is the same as the size of the tumor before administration. As used herein, stabilization refers to a tumor that changes in size by ±5% after administration compared to the tumor size before administration.

[0092] In embodiments, the treatment increases the overall response rate (ORR) compared to the ORR in otherwise similar patients with cancer who have not been treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment increases the ORR by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% (including any value or range therebetween). In embodiments, treatment according to the methods of the present disclosure increases the ORR by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, 650%, about 700%, about 750%, about 800%, about 850%, about 900%, about 950%, or about 1000% or more (including all values ​​and ranges therebetween) compared to the ORR in an otherwise similar patient with cancer not treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment increases the ORR by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% (including any value or range therebetween) compared to the ORR of otherwise similar patients with cancer who have not been treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment increases the ORR by at least about 5% compared to the ORR of otherwise similar patients with cancer who have not been treated with Compound I or a pharmaceutically acceptable salt thereof.In embodiments, the treatment improves the ORR by about 5% to about 1000%, about 10% to about 1000%, about 20% to about 1000%, about 30% to about 1000%, about 40% to about 1000%, about 50% to about 1000%, about 60% to about 1000%, about 70% to about 1000%, about 80% to about 1000%, about 90% to about 1000%, about Increase by 100% to about 1000%, about 150% to about 1000%, about 200% to about 1000%, about 250% to about 1000%, about 300% to about 1000%, about 350% to about 1000%, about 400% to about 1000%, about 450% to about 1000%, about 500% to about 1000%, about 600% to about 1000%, about 700% to about 1000%, about 800% to about 1000%, about 900% to about 1000% (including all values ​​and ranges therebetween).

[0093] In embodiments, the treatment increases progression-free survival (PFS) compared to the PFS of otherwise similar patients with cancer who are not treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment extends PFS by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, or at least about 24 months, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years (including any value or range therebetween) compared to the PFS of a similar patient with cancer not treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment extends PFS by at least about 3 months compared to the PFS of an otherwise similar patient with cancer who has not been treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment extends PFS by at least about 6 months, at least 12 months, at least about 18 months, or at least about 24 months compared to the PFS of an otherwise similar patient with cancer who has not been treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment extends PFS by about 1 month to about 5 years, about 2 months to about 5 years, about 4 months to about 5 years, about 6 months to about 5 years, about 8 months to about 5 years, about 10 months to about 5 years, about 12 months to about 5 years, about 18 months to about 5 years, about 24 months to about 5 years, about 3 years to about 5 years, or about 4 years to about 5 years (including any value and range therebetween) compared to the PFS of an otherwise similar patient with cancer who has not been treated with Compound I or a pharmaceutically acceptable salt thereof.

[0094] In embodiments, treatment according to the methods of the present disclosure increases PFS by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 750%, about 800%, about 850%, about 900%, about 950%, or about 1000% or more (including all values ​​and ranges therebetween) compared to the PFS of other similar patients with cancer who are not treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment improves PFS by about 5% to about 1000%, about 10% to about 1000%, about 20% to about 1000%, about 30% to about 1000%, about 40% to about 1000%, about 50% to about 1000%, about 60% to about 1000%, about 70% to about 1000%, about 80% to about 1000%, about 90% to about 1000%, about 100% to about 1000%, or about 100% compared to the PFS of similar patients with cancer who are not treated with Compound I or a pharmaceutically acceptable salt thereof. % to about 1000%, about 150% to about 1000%, about 200% to about 1000%, about 250% to about 1000%, about 300% to about 1000%, about 350% to about 1000%, about 400% to about 1000%, about 450% to about 1000%, about 500% to about 1000%, about 600% to about 1000%, about 700% to about 1000%, about 800% to about 1000%, and about 900% to about 1000% (including all values ​​and ranges therebetween).

[0095] In embodiments, the treatment increases overall survival (OS) compared to the OS of otherwise similar patients with cancer who have not been treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, the treatment increases OS by at least about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks, or about 7 weeks, or about 8 weeks, or about 9 weeks, or about 10 weeks, or about 1 month, or about 2 months, or about 3 months, or about 4 months, or about 5 months, or about 6 months, or about 7 months, or about 8 months, compared to the OS of otherwise similar patients with cancer who have not been treated with Compound I or a pharmaceutically acceptable salt thereof. or about 9 months, or about 10 months, or about 11 months, or about 12 months, or about 13 months, or about 14 months, or 15 months, or about 16 months, or about 17 months, or about 18 months, or about 19 months, or about 20 months, or about 21 months, or about 22 months, or about 23 months, or about 24 months, or about 3 years, or about 4 years, or about 5 years, or about 6 years, or about 7 years, or about 8 years, or about 9 years, or about 10 years (including any value and range therebetween). In embodiments, the treatment increases OS by at least about 3 months compared to the OS of an otherwise similar patient with cancer who is not treated with Compound I or a pharmaceutically acceptable salt thereof. In embodiments, treatment according to the methods of the present disclosure increases OS by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 750%, about 800%, about 850%, about 900%, about 950%, or about 1000% or more (including all values ​​and ranges therebetween) compared to OS in otherwise similar patients with cancer who are not treated with Compound I or a pharmaceutically acceptable salt thereof.In embodiments, the treatment improves OS by about 5% to about 1000%, about 10% to about 1000%, about 20% to about 1000%, about 30% to about 1000%, about 40% to about 1000%, about 50% to about 1000%, about 60% to about 1000%, about 70% to about 1000%, about 80% to about 1000%, about 90% to about 1000%, about 100% to about 1000%, about 110% to about 1000%, about 120% to about 1000%, about 130% to about 1000%, about 140% to about 1000%, about 150% to about 1000%, about 160% to about 1000%, about 170% to about 1000%, about 180% to about 1000%, about 190% to about 1000%, about 210% to about 1000%, about 220% to about 1000%, about 230% to about 1000%, about 240% to about 1000%, about 250% to about 1000%, about 260% to about 1000%, about 270% to about 1000%, about 280% to about 1000%, about 290% to about 1000%, about 300% to about 1000%, about 310% to about 1000%, about 320% to about 1000%, about 330% to about 1000%, about 340% to about 1000%, about 350% to about 1000%, about 360% to about 1000%, about 370% to about Increase by 0% to about 1000%, about 150% to about 1000%, about 200% to about 1000%, about 250% to about 1000%, about 300% to about 1000%, about 350% to about 1000%, about 400% to about 1000%, about 450% to about 1000%, about 500% to about 1000%, about 600% to about 1000%, about 700% to about 1000%, about 800% to about 1000%, about 900% to about 1000% (including all values ​​and ranges therebetween).

[0096] Numbered Embodiments 1. A method for treating advanced or metastatic cancer, comprising administering about 5 mg to about 1500 mg of Compound I having the following chemical structure: [ka] or an equivalent dose of a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0097] 2. The method of embodiment 1, wherein an equivalent dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered.

[0098] 3. The method of embodiment 1, wherein an equivalent dose of about 20 mg to about 1000 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

[0099] 4. The method of embodiment 1, wherein an equivalent dose of about 40 mg to about 1000 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

[0100] 5. The method of embodiment 1, wherein an equivalent dose of about 1000 mg of Compound I, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered.

[0101] 6. The method of any one of embodiments 1-5, wherein the equivalent dose of Compound I, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered once a day or twice a day.

[0102] 7. The method of embodiment 6, wherein an equivalent dose of about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0103] 8. The method of embodiment 6, wherein an equivalent dose of about 250 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0104] 9. The method of embodiment 6, wherein an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

[0105] 10. The method according to any one of embodiments 1 to 9, wherein the equivalent dose of compound I, or a pharmaceutically acceptable salt or stereoisomer thereof, is administered orally in the form of a pharmaceutical formulation.

[0106] 11. The method of embodiment 10, wherein the pharmaceutical formulation is a tablet or capsule.

[0107] 12. The method of embodiment 11, wherein the pharmaceutical formulation is a capsule.

[0108] 13. The method of any one of embodiments 10-12, wherein the pharmaceutical formulation comprises an equivalent dose of about 5 mg to about 50 mg of Compound I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0109] 14. The method according to any one of embodiments 10 to 12, wherein the pharmaceutical formulation comprises about 10 mg or about 25 mg of compound I, or an equivalent dose of a pharmaceutically acceptable salt or stereoisomer thereof.

[0110] 15. The cancer is Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumor, primary CNS tumor, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumor (metastasis to the central nervous system of a tumor arising outside the central nervous system), brain tumor, brain metastasis, colorectal cancer, colorectal cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, 15. The method of any one of embodiments 1-14, wherein the cancer is chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, melanoma, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), esophageal cancer, bladder cancer, mesothelioma, or thyroid cancer.

[0111] 16. The method of embodiment 15, wherein the cancer is non-small cell lung cancer (NSCLC), colon cancer, melanoma, or pancreatic cancer.

[0112] 17. The method of any one of embodiments 1 to 16, wherein the cancer comprises a solid tumor harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway.

[0113] 18. The method of embodiment 17, wherein the one or more abnormalities are KRAS mutation, NRAS mutation, HRAS mutation, BRAF mutation, BRAF fusion, BRAF rearrangement, ARAF mutation, RAF mutation, increased receptor tyrosine kinase (RTK) signaling, RAS gene amplification, RAF gene amplification, or a combination thereof.

[0114] 19. The method of embodiment 18, wherein the KRAS mutation is G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof.

[0115] 20. The method of embodiment 18, wherein the NRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0116] 21. The method of embodiment 18, wherein the HRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0117] 22. The method of embodiment 18, wherein the ARAF mutation comprises G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

[0118] 23. The method of embodiment 18, wherein the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof.

[0119] 24. The method of embodiment 18, wherein the BRAF mutation comprises a class 2 or 3 BRAF mutation.

[0120] 25. The method of embodiment 18, wherein the BRAF mutations comprise V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

[0121] 26. The method of embodiment 18, wherein the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof.

[0122] 27. The method of embodiment 18, wherein the one or more abnormalities include NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

[0123] 28. The compound I is [ka] 28. The method of any one of embodiments 1 to 27, wherein

[0124] 29. The method of embodiment 28, wherein the compound has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0125] 30. A method of treating cancer harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway in a subject, comprising: detecting said one or more abnormalities in said MAPK pathway; and then About 5 mg to about 1500 mg of Compound I having the following chemical structure: [ka] or an equivalent dose of a pharmaceutically acceptable salt thereof to a subject.

[0126] 31. The method of embodiment 30, wherein about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered.

[0127] 32. The method of embodiment 30, wherein an equivalent dose of about 20 mg to about 1000 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

[0128] 33. The method of embodiment 30, wherein an equivalent dose of about 40 mg to about 1000 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

[0129] 34. The method of embodiment 30, wherein an equivalent dose of about 1000 mg of compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

[0130] 35. The method of embodiment 30, wherein the one or more abnormalities are KRAS mutation, NRAS mutation, HRAS mutation, BRAF mutation, BRAF fusion, BRAF rearrangement, ARAF mutation, RAF mutation, increased receptor tyrosine kinase (RTK) signaling, RAS gene amplification, RAF gene amplification, or a combination thereof.

[0131] 36. The method of embodiment 35, wherein the KRAS mutation is G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof.

[0132] 37. The method of embodiment 35, wherein the NRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0133] 38. The method of embodiment 35, wherein the HRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

[0134] 39. The method of embodiment 35, wherein the ARAF mutation comprises G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

[0135] 40. The method of embodiment 35, wherein the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof.

[0136] 41. The method of embodiment 35, wherein the BRAF mutation comprises a class 2 or 3 BRAF mutation.

[0137] 42. The method of embodiment 35, wherein the BRAF mutations comprise V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

[0138] 43. The method of embodiment 35, wherein the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof.

[0139] 44. The method of embodiment 30, wherein the one or more abnormalities include NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

[0140] 45. The cancer is Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumor, primary CNS tumor, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumor (metastasis to the central nervous system of a tumor arising outside the central nervous system), brain tumor, brain metastasis, colorectal cancer, colorectal cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, The method of any one of embodiments 30 to 44, wherein the cancer is chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, melanoma, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), esophageal cancer, bladder cancer, mesothelioma, or thyroid cancer.

[0141] 46. ​​The method of embodiment 45, wherein the cancer is non-small cell lung cancer (NSCLC), colon cancer, melanoma, or pancreatic cancer.

[0142] 47. The compound I is [ka] 47. The method of any one of embodiments 30 to 46, wherein

[0143] 48. The method of embodiment 47, wherein the compound has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

[0144] 49. The method of any one of embodiments 30-48, wherein the treatment reduces the size of the tumor compared to the size of the tumor before administration.

[0145] 50. The method of embodiment 49, wherein the treatment reduces the tumor size by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% compared to the tumor size before administration.

[0146] 51. The method of any one of embodiments 30-48, wherein said treatment increases the overall response rate (ORR) compared to the ORR in otherwise similar patients with cancer who have not been treated with compound I.

[0147] 52. The method of embodiment 51, wherein said treatment increases said ORR by at least about 5%.

[0148] 53. The method of embodiment 52, wherein said treatment increases said ORR by at least 10% to about 100%.

[0149] 54. The method according to any one of embodiments 30 to 48, wherein said treatment increases the progression-free survival (PFS) compared to the PFS of otherwise similar patients with cancer who have not been treated with said compound I.

[0150] 55. The method of embodiment 54, wherein said treatment extends said PFS by at least about 3 months.

[0151] 56. The method of embodiment 55, wherein said treatment extends said PFS by at least about 6 months, 12 months, at least about 18 months, or at least about 24 months.

[0152] 57. The method of any one of embodiments 30 to 48, wherein said treatment increases overall survival (OS) compared to OS in otherwise similar patients with cancer who are not treated with said compound I.

[0153] 58. The method of embodiment 57, wherein the treatment extends the OS by at least about 3 months. [Example]

[0154] Example 1. Compound I is a potent pan-RAF inhibitor.

[0155] To evaluate the ability of compound I to inhibit various RAF kinases, the IC 50 Values ​​were measured using two different biochemical cell-free kinase assays: the RBC radiometric HotSpot™ filter-based kinase assay (reaction biology; reaction components included 15–25 μM ATP, 3–200 nM recombinant kinase, and 5 μM kinase-dead MEK1 K97R substrate) and the PanQinase™ flashplate-based kinase assay (reaction biology; 0.25–0.5 μg / 50 μL kinase-dead MEK K97M substrate and 0.1–3 μM ATP were added according to the manufacturer's protocol).

[0156] The inhibitory effect of Compound I on wild-type ARAF, BRAF, and CRAF kinase isoforms and specifically designed mutant forms of ARAF (P462L, G377R, G387D, del 347-348, and del 347-348+G387D), BRAF (V600E, G469A, Fusion-FAM131B), and CRAF (dimer-RAF1 and R391W) was tested. The results demonstrated that Compound I is a pan-inhibitor of all three RAF isoforms and selected mutants with nanomolar IC 50 These ICs are shown in the range. 50 The values ​​are shown in Table 1 (measured using the HopSpot filter-based assay platform) and Table 2 (average IC measured using the PanQinase™ flashplate-based assay platform). 50 ) [Table 2] [Table 3]

[0157] To assess the potency and selectivity of Compound I against different RAF mutants, the mean IC of Compound I against RAF kinase isoforms and their mutants was calculated. 50 values ​​and further measured the mean IC values ​​of other known pan-inhibitors, velbarafenib and naporafenib, by using the PanQinase™ flashplate-based kinase assay with 0.25-0.5 μg / 50 μL of kinase-killed MEK K97M substrate and 0.1-3 μM ATP. 50 Compared with IC 50 The values ​​are summarized in Table 3. As shown in Table 3, compound I was a significantly more potent inhibitor (3-5-fold lower IC) than belbarafenib or naporafenib against all three RAF isoforms, especially those containing the ARAF P462L and ARAF G377R mutant kinase variants. 50 value). [Table 4]

[0158] Example 2. Preclinical study to determine the dose of Compound I Compound I was evaluated in GLP-compliant 28-day oral toxicity studies in two preclinical species, Sprague Dawley rats and beagle dogs. In the 28-day rat study, Compound I was administered by oral gavage once daily at 0, 10, 20, or 45 mg / kg / day. No mortality, clinical signs, changes in body weight or food intake, ophthalmology, clinical pathology, or gross or microscopic findings of toxicological relevance were observed. In the 28-day rat study, Compound I was administered by oral gavage once daily at 0, 3.75, 7.5, or 15 mg / kg / day. No mortality, clinical signs, changes in body weight or food intake, ophthalmology, ECG, clinical pathology, or gross or microscopic findings of toxicological relevance were observed.

[0159] PK / PD / efficacy simulations were used to predict the effective human dose (500 mg / dose BID) and human PK parameters (allometrically scaled CL of 1.2 mL / min / kg, Vss of 0.77 L / kg, assumed oral %F of approximately 40%, and unbound plasma Ctau of Compound I of approximately 15 nM).

[0160] Example 3. Preclinical efficacy evaluation of Compound I in tumor xenograft mouse models. The tumor growth inhibitory effect of compound I was evaluated in xenograft mouse models bearing pathogenic RAS (NRAS and KRAS) and RAF (BRAF class 2 / 3) mutation-driven colon cancer, non-small cell lung cancer, melanoma, and ovarian cancer. As shown in Figure 1A-E, a dose-dependent tumor growth inhibitory effect of compound I was observed.

[0161] Example 4. A Phase 1 Study of Oral Capsules of Compound I to Investigate the Safety, Dosing, and Antitumor Activity of Compound I in Adult Participants with Advanced or Metastatic Solid Tumors Harboring Mitogen-Activated Protein Kinase (MAPK) Pathway Aberrations

[0162] This is a Phase 1 study of Compound I in participants with advanced or metastatic solid tumors harboring MAPK pathway abnormalities. The study consists of two parts: dose-finding (Part A) and expansion (Part B). The study design is summarized in Figure 2.

[0163] Part A

[0164] Primary Objective (Part A): To determine the Phase 2 dose (RP2D) and / or maximum tolerated dose (MTD) of Compound I. To determine the Phase 2 dose (RP2D) and / or maximum tolerated dose (MTD) of Compound I that can be safely administered to participants with advanced and / or metastatic solid tumors with MAPK pathway abnormalities; To characterize the safety profile of Compound I.

[0165] Secondary Objectives (Part A): To characterize the plasma PK of Compound I and its metabolites; to characterize the dose proportionality of Compound I and its metabolites; and to evaluate antitumor activity.

[0166] Exploratory Objectives (Part A): To explore pharmacodynamics and ctDNA biomarkers; to investigate the effect of Compound I on QTc and other ECG parameters after oral administration of Compound I; to characterize the urinary PK of Compound I and its metabolites (if applicable); to perform preliminary Compound I metabolite identification in plasma and urine samples; to evaluate antitumor activity; to assess duration of response (DoR) and progression-free survival (PFS); and to investigate the effect of food on the plasma PK of Compound I.

[0167] Endpoints (Part A): a. Incidence and nature of dose-limiting toxicities (DLTs) (Maximum Tolerated Dose (MTD)-Determining Cohort in Part A only) b. The incidence and severity of adverse events (AEs) and serious adverse events (SAEs), laboratory values, vital signs, and changes in other safety measures c. Dose interruption and reduction d. Plasma PK parameters of Compound I and its metabolites, including but not limited to Cmax, Tmax, AUC∞, AUCtau, t1 / 2, CL / F (Compound I only), Vz / F (Compound I only), accumulation ratio, metabolite-to-parent ratio (if applicable) e. Plasma concentrations of Compound I and its metabolites f. Dose proportionality of Compound I and its metabolites as determined by the slopes of Cmax and AUC and associated 90% CI g. Objective overall response rate (ORR) is defined as confirmed complete response (CR) + partial response (PR) per RECIST v1.1. h. Changes from baseline in intratumoral and / or peripheral blood mononuclear cell MAPK signaling and ctDNA levels i. Corrected QT interval (QTc) and change in QTc interval from baseline j. PR interval and change in PR interval from baseline k. QRS interval and change in QRS interval from baseline l. Heart rate and change in heart rate from baseline m. Urinary PK parameters of Compound I and its metabolites (if applicable), including but not limited to excretion (Ae), renal clearance (CLr), if applicable. n. Preliminary structures of Compound I metabolites in plasma and urine Disease control rate defined as best overall response (BOR) + complete response (CR) + partial response (PR) of stable disease p. Duration of response (DOR) q.Progression-free survival (PFS) r. Effect of food on the plasma PK of Compound I as determined by the 90% CI of plasma Cmax, ss, and AUCtau in the fed and fasted states

[0168] Part B

[0169] Primary Objective (Part B): To further evaluate the antitumor activity of Compound I at the RP2D in different tumor / mutation types; and to further characterize the safety profile of Compound I at the RP2D.

[0170] Secondary Objectives (Part B): To evaluate PFS and OS.

[0171] Exploratory Objectives (Part B): To evaluate antitumor activity; to investigate PD and ctDNA, biomarkers; and to characterize the plasma PK of Compound I and its metabolites (if applicable).

[0172] Endpoints (Part B): a.ORR defined as confirmed CR+PR by RECIST v1.1 b.DoR c. Incidence and severity of AEs and SAEs, laboratory values, vital signs, and changes in other safety measures d. Dose interruption and reduction e.PFS and OS f.Disease control rate defined as BOR of SD+CR+PR g. Changes from baseline in intratumoral and / or peripheral blood mononuclear cell MAPK signaling and ctDNA levels h. Plasma concentrations of Compound I and its metabolites (if applicable)

[0173] The study will consist of three periods: (i) a screening period (up to 28 days before the treatment period); (ii) a treatment period (treatment cycle length is 28 days); and (iii) a follow-up period (safety follow-up visit 30 (± 3) days after the last dose of Compound I). Participants will be followed up by telephone every 12 weeks ± 1 week from the end of treatment until death, withdrawal of consent, or loss to follow-up.

[0174] Inclusion criteria for patients

[0175] A participant is eligible to participate in the study only if all of the following criteria apply: a. Participants must be 18 years of age or older at the time of signing the informed consent. b. Participants with a histologic or cytologic diagnosis of advanced or metastatic solid tumors with documented clinically significant MAPK pathway abnormalities. Participants must have exhausted all available standard therapies or, in the investigator's opinion, are unlikely to tolerate or derive clinically meaningful benefit from available standard treatment regimens. c. Performance status (ECOG) of 0 or 1 measured within 72 hours prior to treatment initiation d. Have measurable disease by RECIST v1.1 e. The tumor must be safely amenable to core needle or excision biopsy. f. Kidney: creatinine clearance ≥ 60 mL / min; Liver: total bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN if due to tumor involvement of the liver; Bone marrow: hemoglobin ≥ 9.0 g / dL; platelets ≥ 100 × 109 cells / L; absolute neutrophil count ≥ 1.5 × 109 cells / L). g. Expected life expectancy of at least 12 weeks h. For each arm of Part B (expansion), participants must be diagnosed with tumor type(s) harboring the specified mutation(s). For Arm 1 (NRASQ61-mutated melanoma), participants must have received prior immunotherapy (except contraindications). For Arm 2 (KRASG12C-mutated NSCLC), participants must have received platinum-based combination therapy and / or targeted therapy (if applicable) directed against EGFR, KRAS, ALK, or ROS1 mutations, or PD-L1 expression (except contraindications). i. Men and women must agree to use contraception.

[0176] Exclusion criteria: Known uncontrolled brain metastases. Stable brain metastases are permitted if they have been or are being treated with a stable dose of steroids / anticonvulsants with no change in dose in the past 4 weeks. b. Active fungal, bacterial, and / or known viral infections, including HIV or Hepatitis A, B, or C Concurrent malignancies or a history of malignancies with a disease-free interval of less than 2 years at the time of enrollment (excluding adequately treated non-metastatic, non-melanoma skin cancer, carcinoma in situ, melanoma in situ, and prostate cancer with an undetectable PSA). Other concomitant malignancies that are indolent and not requiring active treatment should be discussed with the medical monitor prior to enrollment. d. Clinically significant (i.e., ongoing) cardiovascular disease: cerebrovascular accident / stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (>New York Heart Association Class II), QTc ≥ 470 msec, or serious arrhythmia requiring medication. e. Uncontrolled or severe intercurrent medical conditions. f. Gastrointestinal conditions that may impair absorption of the study intervention (specific cases may be enrolled after consultation with the sponsor), or the inability to take the study intervention. g. Received any cancer-directed therapy (chemotherapy, hormonal therapy, biological therapy, etc.) within 28 days or 5 half-lives (whichever is shorter) of the start of the study intervention. Participants who received radiation therapy must have recovered from treatment-related acute toxicity. h. Use of any product or medication known to be a strong or moderate inducer or inhibitor of CYP3A4 that cannot be discontinued for at least 4 weeks. i. Use of proton pump inhibitors and histamine-2 receptor antagonists, which cannot be discontinued at least 2 weeks before the first dose. j. Use of combination therapy.

[0177] design:

[0178] Exam Part A The maximum tolerated dose (MTD) in participants with solid tumors harboring MAPK abnormalities will be determined based on the incidence of dose-limiting toxicity (DLT). The DLT observation period will be cycle 1 (28 days). DLT determination will be based on a regimen in which participants receive Compound I daily. Based on safety data / DLT and PK data, the Safety Review Committee (SRC) may decide that additional dose escalation should not be investigated and / or that the determination of the MTD should be stopped. The starting dose level of Compound I (dose level 1) is 20 mg BID. After at least three evaluable participants have been treated at dose level 1, a dose search will be conducted to investigate up to five additional dose levels as described herein.

[0179] Exam Part B

[0180] Part B includes multiple non-randomized expansion arms defined by MAPK aberration and / or tumor type, treated at the recommended Phase 2 dose (RP2D).

[0181] The Part B arms are as follows: Arm 1: NRAS Q61 mutant melanoma Arm 2: KRAS G12C mutant NSCLC Arm 3: KRAS-mutated solid tumors Arm 4: BRAF class 1 mutant solid tumors Arm 4: BRAF class 2 / 3 mutant solid tumors

[0182] Exemplary MAPK abnormalities are listed in Table 4. [Table 5] [Table 6-1] [Table 6-2] [Table 7] [Table 8] [Table 9] [Table 10-1] [Table 10-2]

[0183] Compound I (i.e., (S)-5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one) will be administered orally to participants BID in capsule formulations at unit dose strengths of 10 mg or 25 mg in the morning and evening, approximately 12 hours apart. Specifically, in Part A, Compound I will be administered as a single dose on Day 1 of Cycle 1, with no doses administered on Days 2 and 3, followed by BID dosing on Days 4 and beyond. Based on PK data, QD dosing will also be investigated in Part A, where Compound I will be administered as a single dose on Day 1 of Cycle 1, with no doses administered on Days 2 and 3, followed by QD dosing on Days 4 and beyond.

[0184] Efficacy evaluation

[0185] Tumor response to treatment will be assessed by the investigator using RECIST v1.1. Tumor assessments will be performed by CT / MRI / PE at screening, on Day 1 of Cycle 3 (Day 57), every 2 cycles (56 days), and then every 3 cycles (Day 84) until Day 1 of Cycle 13, and then at the end-of-treatment visit. Tumor assessments will include all known or suspected disease sites. Imaging must include CT or MRI scans of the chest, abdomen, and pelvis. Imaging will be performed at the abdomen, chest, pelvis, and if the primary tumor is located elsewhere.

[0186] Safety will be assessed by performing the following: physical examination, vital signs, electrocardiogram, dermatological examination, and clinical safety laboratory assessments.

[0187] Example 5. Safety and Efficacy Evaluation of Compound I in Human Cancer Patients Dosing Regimen: To evaluate the safety and efficacy of Compound I in cancer treatment, participants were administered Compound I orally at 20 mg BID ("Bisindai," or "twice daily"), 30 mg BID, 50 mg BID, 50 mg QD ("Quakudai," or "once daily"), 75 mg BID, or 100 mg QD for a set period. Treatment-related adverse events (TRAEs, grade ≤ 2 and grade ≥ 3) were monitored and recorded. The efficacy of Compound I in cancer treatment was determined using radiological tumor assessment (e.g., PET-CT or MRI scan) according to RECIST v1.1.

[0188] Results: Participant (n=1) with metastatic NRASQ61-mutated melanoma achieved a partial response (PR) with a 61% reduction in target lesions after 2 months of Compound I at 50 mg QD, and this PR was confirmed with a 69% reduction in target lesions after 4 months, resulting in significant resolution of PET avidity (Figure 3).

[0189] Additional dosing regimens of the compounds are considered (summarized in Table 5). [Table 11]

Claims

1. 1. A method for treating advanced or metastatic cancer, comprising administering to a patient from about 5 mg to about 500 mg of Compound I: 【Chemistry 1】 or an equivalent dose of a pharmaceutically acceptable salt thereof to a subject in need thereof.

2. 10. The method of claim 1, wherein an equivalent dose of about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, or about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered.

3. 10. The method of claim 1, wherein an equivalent dose of about 20 mg to about 1000 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

4. 10. The method of claim 1, wherein an equivalent dose of about 20 mg to about 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

5. 10. The method of claim 1, wherein an equivalent dose of about 20 mg to about 200 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

6. 10. The method of claim 1, wherein an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.

7. 7. The method of claim 6, wherein an equivalent dose of about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

8. 7. The method of claim 6, wherein an equivalent dose of about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

9. 7. The method of claim 6, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

10. 7. The method of claim 6, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

11. 7. The method of claim 6, wherein an equivalent dose of about 75 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

12. 7. The method of claim 6, wherein an equivalent dose of about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

13. 7. The method of claim 6, wherein an equivalent dose of about 250 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

14. 7. The method of claim 6, wherein an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

15. The method according to any one of claims 1 to 14, wherein an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered orally in the form of a pharmaceutical formulation.

16. 16. The method of claim 15, wherein the pharmaceutical formulation is a tablet or capsule.

17. 17. The method of claim 16, wherein the pharmaceutical formulation is a capsule.

18. 18. The method of any one of claims 15 to 17, wherein the pharmaceutical formulation comprises an equivalent dose of about 5 mg to about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof.

19. 18. The method of any one of claims 15 to 17, wherein the pharmaceutical formulation comprises an equivalent dose of about 10 mg to about 25 mg of Compound I, or a pharmaceutically acceptable salt thereof.

20. The cancer is Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumor, primary CNS tumor, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumor (metastasis of a tumor arising outside the central nervous system to the central nervous system), brain tumor, brain metastasis, colorectal cancer, colorectal cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myeloid leukemia, thyroid cancer ... The method of any one of claims 1 to 19, wherein the cancer is myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, melanoma, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), esophageal cancer, bladder cancer, mesothelioma, or thyroid cancer.

21. 21. The method of claim 20, wherein the cancer is non-small cell lung cancer (NSCLC), colon cancer, melanoma, or pancreatic cancer.

22. 22. The method of any one of claims 1 to 21, wherein the cancer comprises a solid tumor harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway.

23. 23. The method of claim 22, wherein the one or more abnormalities are KRAS mutation, NRAS mutation, HRAS mutation, BRAF mutation, BRAF fusion, BRAF rearrangement, ARAF mutation, RAF mutation, increased receptor tyrosine kinase (RTK) signaling, RAS gene amplification, RAF gene amplification, or a combination thereof.

24. 24. The method of claim 23, wherein the KRAS mutation is G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof.

25. 24. The method of claim 23, wherein the NRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

26. 24. The method of claim 23, wherein the HRAS mutation comprises Q61R, Q61K, Q61L, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

27. 24. The method of claim 23, wherein the ARAF mutation comprises G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

28. 24. The method of claim 23, wherein the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof.

29. 24. The method of claim 23, wherein the BRAF mutation comprises a class 2 or 3 BRAF mutation.

30. 24. The method of claim 23, wherein the BRAF mutation comprises V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

31. 24. The method of claim 23, wherein the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof.

32. 24. The method of claim 23, wherein the one or more abnormalities include NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

33. The compound I is 【Chemistry 2】 The method according to any one of claims 1 to 32, wherein

34. 34. The method of claim 33, wherein the compound has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

35. 1. A method of treating cancer harboring one or more abnormalities in the mitogen-activated protein kinase (MAPK) pathway in a subject, comprising: detecting said one or more abnormalities in said MAPK pathway; and About 5 mg to about 1500 mg of Compound I, having the following chemical structure: 【Transformation 3】 or an equivalent dose of a pharmaceutically acceptable salt thereof to said subject.

36. 36. The method of claim 35, wherein an equivalent dose of about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, or about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered.

37. 36. The method of claim 35, wherein an equivalent dose of about 20 mg to about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

38. 36. The method of claim 35, wherein an equivalent dose of about 40 mg to about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

39. 36. The method of claim 35, wherein an equivalent dose of about 20 mg to 200 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

40. 36. The method of claim 35, wherein an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.

41. 41. The method of claim 40, wherein an equivalent dose of about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

42. 41. The method of claim 40, wherein an equivalent dose of about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

43. 41. The method of claim 40, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

44. 41. The method of claim 40, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

45. 41. The method of claim 40, wherein an equivalent dose of about 75 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

46. 41. The method of claim 40, wherein an equivalent dose of about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

47. 41. The method of claim 40, wherein an equivalent dose of about 250 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

48. 41. The method of claim 40, wherein an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

49. 36. The method of claim 35, wherein the one or more abnormalities are KRAS mutation, NRAS mutation, HRAS mutation, BRAF mutation, BRAF fusion, BRAF rearrangement, ARAF mutation, RAF mutation, increased receptor tyrosine kinase (RTK) signaling, RAS gene amplification, RAF gene amplification, or a combination thereof.

50. 50. The method of claim 49, wherein the KRAS mutation is G12C, G12D, G12R, G12V, G12W, G13C, G13D, G13R, G13V, G13W, Q61R, Q61K, Q61L, Q61H, Q61P, A146P, A146T, A146V, A59G, A59T, R68S, H95D, H95Q, H95R, Y96C, or a combination thereof.

51. 50. The method of claim 49, wherein the NRAS mutation comprises Q61R, Q61K, Q61L, Q61H, Q61P, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

52. 50. The method of claim 49, wherein the HRAS mutation comprises Q61R, Q61K, Q61L, G12S, G12D, G12C, G12V, G12A, G12R, G13V, G13R, G13D, G13C, or a combination thereof.

53. 50. The method of claim 49, wherein the ARAF mutation comprises G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

54. 50. The method of claim 49, wherein the BRAF mutation comprises a class 1 BRAF mutation, a class 2 BRAF mutation, a class 3 BRAF mutation, or a combination thereof.

55. 50. The method of claim 49, wherein the BRAF mutation comprises a class 2 or 3 BRAF mutation.

56. 50. The method of claim 49, wherein the BRAF mutation comprises V600E, V600M, V600G, V600K, V600R, V600D, G469A, G469V, G469R, K601E, K601N, K601T, L597Q, L597V, G464V, G464E, D594N, D594G, D594A, D594H, G466A, G466E, N581S, N581I, G469E, S467L, G596D, G596R, F595L, V459L, D287H, or a combination thereof.

57. 50. The method of claim 49, wherein the RAF mutation comprises S257L / W, S259F, R391S / W, or a combination thereof.

58. 36. The method of claim 35, wherein the one or more abnormalities include NRAS Q61K, KRAS G12C, KRAS G13D, KRAS Q61K, or a combination thereof.

59. The cancer is Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumor, primary CNS tumor, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumor (metastasis of a tumor arising outside the central nervous system to the central nervous system), brain tumor, brain metastasis, colorectal cancer, colorectal cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myeloid leukemia, thyroid cancer ... The method of any one of claims 35 to 58, wherein the cancer is myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, melanoma, neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), esophageal cancer, bladder cancer, mesothelioma, or thyroid cancer.

60. 60. The method of claim 59, wherein the cancer is non-small cell lung cancer (NSCLC), colon cancer, melanoma, or pancreatic cancer.

61. The compound I is 【Chemistry 4】 The method according to any one of claims 35 to 60, wherein

62. 62. The method of claim 61, wherein the compound has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 99%.

63. 63. The method of any one of claims 35 to 62, wherein the treatment reduces the size of the tumor compared to the size of the tumor before administration.

64. 64. The method of claim 63, wherein the treatment reduces the size of the tumor by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% compared to the tumor size before administration.

65. 65. The method of any one of claims 35-64, wherein the treatment increases the overall response rate (ORR) compared to the ORR in otherwise similar patients with cancer who are not treated with Compound I.

66. 66. The method of claim 65, wherein the treatment increases the ORR by at least about 5%.

67. 67. The method of claim 66, wherein the treatment increases the ORR by at least 10% to about 100%.

68. 65. The method of claims 35-64, wherein said treatment prolongs progression-free survival (PFS) compared to the PFS of otherwise similar patients with cancer who are not treated with compound I.

69. 69. The method of claim 68, wherein the treatment extends the PFS by at least about 3 months.

70. 70. The method of claim 69, wherein the treatment extends the PFS by at least about 6 months, 12 months, at least about 18 months, or at least about 24 months.

71. 65. The method of any one of claims 35-64, wherein said treatment increases overall survival (OS) compared to the OS of otherwise similar patients with cancer who are not treated with compound I.

72. 72. The method of claim 71, wherein the treatment increases the OS by at least about 3 months.

73. 1. A method of treating a cancer expressing one or more ARAF mutants in a patient in need thereof, comprising: About 5 mg to about 1500 mg of Compound I, having the following chemical structure: 【Transformation 5】 or an equivalent dose of a pharmaceutically acceptable salt thereof to a subject in need thereof.

74. 74. The method of claim 73, wherein the ARAF mutant comprises a mutation of G331C, A225V, F351L, P539H, Q347_A348del, N217I, G322S, A451T, R255Gfs(Ter)37, S214(Ter), P8Lfs(Ter)26, G387N / D / R / S, P462L, G377R, or a combination thereof.

75. 75. The method of claim 73 or 74, wherein the ARAF mutant comprises a mutation of P462L, G377R, G387D, or a combination thereof.

76. 76. The method of claims 73-75, wherein the compound I or a pharmaceutically acceptable salt thereof is administered at a dose that provides a steady-state plasma concentration sufficient to inhibit the activity of the ARAF mutant.

77. 77. The method of any one of claims 73 to 76, wherein an equivalent dose of about 10 mg to about 300 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

78. 78. The method of claim 77, wherein an equivalent dose of about 20 mg to about 200 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

79. 74. The method of claim 73, wherein an equivalent dose of about 5 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 75 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 325 mg, about 375 mg, about 425 mg, about 475 mg, about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered per day.

80. 74. The method of claim 73, wherein an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.

81. 81. The method of claim 80, wherein an equivalent dose of about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

82. 81. The method of claim 80, wherein an equivalent dose of about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

83. 81. The method of claim 80, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

84. 81. The method of claim 80, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

85. 81. The method of claim 80, wherein an equivalent dose of about 75 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

86. 81. The method of claim 80, wherein an equivalent dose of about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

87. 81. The method of claim 80, wherein an equivalent dose of about 250 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

88. 81. The method of claim 80, wherein an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

89. 1. A method of treating belvarafenib-resistant cancer in a patient in need thereof, comprising: About 5 mg to about 1500 mg of Compound I, having the following chemical structure: 【Transformation 6】 or an equivalent dose of a pharmaceutically acceptable salt thereof to said patient.

90. 90. The method of claim 89, wherein the belbalafenib-resistant cancer comprises an ARAF mutant.

91. 91. The method of claim 89 or 90, wherein the ARAF mutant comprises a mutation of P462L, G377R, G387D, or a combination thereof.

92. 90. The method of claim 89, wherein an equivalent dose of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily.

93. 93. The method of claim 92, wherein an equivalent dose of about 20 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

94. 93. The method of claim 92, wherein an equivalent dose of about 30 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

95. 93. The method of claim 92, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

96. 93. The method of claim 92, wherein an equivalent dose of about 50 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

97. 93. The method of claim 92, wherein an equivalent dose of about 75 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

98. 93. The method of claim 92, wherein an equivalent dose of about 100 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered once daily.

99. 93. The method of claim 92, wherein an equivalent dose of about 250 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

100. 93. The method of claim 92, wherein an equivalent dose of about 500 mg of Compound I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

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